ORPHA: 610;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | Bethlem myopathy 1C | 620726 | Autosomal dominant; Autosomal recessive | 3 | COL6A3 | 120250 |
A number sign (#) is used with this entry because of evidence that Bethlem myopathy-1C (BTHLM1C) is caused by heterozygous mutation in the COL6A3 gene (120250) on chromosome 2q37. Rare cases have been reported with homozygous or compound heterozygous mutations in the COL6A3 gene.
See Ullrich congenital muscular dystrophy-1C (620728), an allelic disorder with a more severe phenotype.
Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. Weakness usually begins in mid-childhood or adolescence, but progression is slow and ambulation is retained into adulthood (summary by Butterfield et al., 2013).
For general phenotypic information and a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1A (158810).
At the 229th ENMC international workshop, Straub et al. (2018) reclassified Bethlem myopathy caused by mutation in one of collagen VI genes as a form of limb-girdle muscular dystrophy. Autosomal dominant forms were designated LGMDD5 (limb-girdle muscular dystrophy, autosomal dominant, 5) and autosomal recessive forms as LGMDR22 (limb-girdle muscular dystrophy, autosomal recessive, 22).
Speer et al. (1996) reported a large family (family 1489) of French Canadian descent in whom 19 of 36 members had Bethlem myopathy. Patients had proximal greater than distal extremity weakness, joint contractures, and childhood onset of symptoms at approximately 2 to 5 years of age. This family was originally reported by Mohire et al. (1988).
Haq et al. (1999) reported a 40-year-old patient in the family reported by Speer et al. (1996) who had severe respiratory muscle involvement, particularly of the diaphragm, which markedly limited his physical functioning and ability to lie supine. EMG confirmed myopathic involvement of limb-girdle and respiratory muscles.
Baker et al. (2007) reported 2 unrelated patients (BM11 and BM2) with Bethlem myopathy and heterozygous mutation in the COL6A3 gene. One patient was a 40-year-old Australian man who had delayed motor development, diffuse muscle weakness, decreased motor capacity, kyphosis, and dystrophic features on muscle biopsy. The other patient was a 20-year-old man who had reduced motor capacity, proximal muscle weakness, joint contractures, and dystrophic findings on muscle biopsy.
Panades-de Oliveira et al. (2019) reported 3 patients from 2 unrelated families (P8A and P9A/9B) with variable manifestations of autosomal recessive Bethlem myopathy-1C due to compound heterozygous or homozygous mutations in the COL6A3 gene. P8A was a 27-year-old woman who presented in childhood with proximal weakness affecting the cervical muscles and muscles of the upper and lower limbs. She also had contractures of the elbows and ankles and reduced maximal expiratory pressure on lung function studies. P9A was a 42-year-old man who presented in childhood with proximal muscle weakness of the lower limbs and distal contractures of the interphalangeal joints and ankles. However, his brother, P9B, did not have muscle weakness at 48 years of age, but had hyperCKemia and distal contractures of the interphalangeal joints and ankles. None of the patients had scoliosis. All patients had increased serum creatine kinase. Muscle biopsies from patients 8A and 9A showed dystrophic features; rimmed vacuoles were also present in the biopsy from P9A.
Villar-Quiles et al. (2021) reported 12 patients from 10 unrelated families with autosomal recessive BTHLM1C who were compound heterozygous for the common missense variant in the COL6A3 gene (K2483E; 120250.0012) and a putative loss-of-function COL6A3 mutation on the other allele (see, e.g., R1597X, 120250.0014). Most of the patients, who ranged in age from 2 to 64 years, presented in early childhood with delayed motor development, axial and proximal muscle weakness, abnormal gait, and difficulty running. Two sibs (family 10) showed decreased fetal movements and presented at birth; 1 patient (P7) presented with symptoms in adulthood. All had contractures variably involving the fingers, wrists, elbows, knees, and ankles. Some had distal joint hyperlaxity, rigid spine, mildly decreased forced vital capacity, and/or follicular hyperkeratosis. All remained ambulatory, although a few walked with a cane. Four additional patients (P11-P14), who were homozygous for the K2483E variant, had a similar phenotype with onset of symptoms in early childhood. Features included foot deformities, steppage or abnormal gait, and proximal and distal muscle weakness. In contrast to the compound heterozygous patients, joint contractures were uncommon, and none had distal hyperlaxity, skin abnormalities, or respiratory involvement. Serum creatine kinase levels were mildly to moderately elevated in all patients. Muscle biopsies showed variable abnormalities, including dystrophic features, fiber size variation, myofibrillar disorganization, autophagic vacuoles, and nemaline rods. Fibroblasts derived from 5 of the compound heterozygous patients showed reduced collagen VI secretion, which was most likely due to the loss-of-function variant. In contrast, fibroblasts from 3 patients who were homozygous for the K2483E variant showed essentially normal collagen VI secretion in 2 and mildly reduced secretion in 1, suggesting that the missense variant does not significantly impact COL6 assembly and secretion.
The transmission pattern of BTHLM1C in the family of French Canadian descent (family 1489) reported by Mohire et al. (1988) and Pan et al. (1998) was consistent with autosomal dominant inheritance.
The transmission pattern of BTHLM1C in families reported by Villar-Quiles et al. (2021) was consistent with autosomal recessive inheritance.
Since collagen genes were postulated as the candidate genes for Bethlem myopathy mapping to chromosome 21, Speer et al. (1996) analyzed the COL6A3 gene region on chromosome 2q. Lod scores of 8.13 and 7.03 were observed between Bethlem myopathy and the markers D2S345 and D2S338. Analysis of chromosome 2 markers permitted localization of the disease gene to a 17-cM interval spanned by D2S336 and D2S395. Fluorescence in situ hybridization studies revealed that the COL6A3 gene was localized between D2S336 and D2S395. Speer et al. (1996) reported that this finding was consistent with the hypothesis that in the Dutch families described by Jobsis et al. (1996) and in the family reported by them, Bethlem myopathy is caused by mutations in different subunits of type VI collagen. Nine kindreds showed genetic linkage to the COL6A1-COL6A2 cluster on 21q22.3, whereas one family, originally reported by Mohire et al. (1988), showed linkage to markers on 2q37 close to COL6A3.
Exclusion Studies
In the family with Bethlem myopathy reported by Mohire et al. (1988), Speer et al. (1995) excluded linkage to the 7-cM LGMD1A (609200) interval on chromosome 5.
In affected members of a large American pedigree of French Canadian descent with Bethlem myopathy-1C, originally reported by Mohire et al. (1988) and mapped to chromosome 2q by Speer et al. (1996), Pan et al. (1998) identified a heterozygous mutation in the COL6A3 gene (G1679E; 120250.0001). The mutation segregated with the disorder in the family.
In 2 unrelated patients with Bethlem myopathy, Baker et al. (2007) identified different heterozygous mutations in the COL6A3 gene (120250.0005; 120250.0006).
In 2 brothers (P9A and P9B), with variable manifestations of autosomal recessive Bethlem myopathy-1C, Panades-de Oliveira et al. (2019) identified a homozygous missense variant in the COL6A3 gene (K2486E; 120250.0012). Another patient (P8A) with the disorder was compound heterozygous for K2486E and a frameshift mutation (c.8540_8540delA; 120250.0013). The mutations were found by next-generation sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed. P9A, a 42-year-old man, had onset of proximal muscle weakness in childhood, whereas his brother (P9B) was almost asymptomatic at 48 years of age, except for hyperCKemia and distal contractures. Another patient (11A) with a similar phenotype carried a homozygous K2486E variant in the COL6A3 gene and a heterozygous splice site mutation in the COL6A1 gene (c.2435-2A-G).
Villar-Quiles et al. (2021) reported 16 patients with autosomal recessive BTHLM1C associated with the K2483E substitution in the COL6A3 gene (120250.0012). Four unrelated patients were homozygous for the mutation, and 12 patients from 10 families carried it in compound heterozygous state with a putative loss-of-function COL6A3 mutation (see, e.g., R1597X, 120250.0014). Segregation studies, performed in 8 families, confirmed that the unaffected parents were heterozygous carriers. Fibroblasts derived from 5 of the compound heterozygous patients showed reduced collagen VI secretion, which was most likely due to the loss-of-function variant. In contrast, fibroblasts from 3 patients who were homozygous for the K2483E variant showed essentially normal collagen VI secretion in 2 and mildly reduced secretion in 1, suggesting that the missense variant does not significantly impact COL6 assembly and secretion.
Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R. Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann. Neurol. 62: 390-405, 2007. [PubMed: 17886299] [Full Text: https://doi.org/10.1002/ana.21213]
Butterfield, R. J., Foley, A. R., Dastgir, J., Asman, S., Dunn, D. M., Zou, Y., Hu, Y., Donkervoort, S., Flanigan, K. M., Swoboda, K. J., Winder, T. L., Weiss, R.B., Bonnemann, C. G. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. Hum. Mutat. 34: 1558-1567, 2013. [PubMed: 24038877] [Full Text: https://doi.org/10.1002/humu.22429]
Haq, R. U., Speer, M. C., Chu, M.-L., Tandan, R. Respiratory muscle involvement in Bethlem myopathy. Neurology 52: 174-176, 1999. [PubMed: 9921869] [Full Text: https://doi.org/10.1212/wnl.52.1.174]
Jobsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F., Bohlhuis, P. A. Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nature Genet. 14: 113-115, 1996. [PubMed: 8782832] [Full Text: https://doi.org/10.1038/ng0996-113]
Mohire, M. D., Tandan, R., Fries, T. J., Little, B. W., Pendlebury, W. W., Bradley, W. G. Early-onset benign autosomal dominant limb-girdle myopathy with contractures (Bethlem myopathy). Neurology 38: 573-580, 1988. [PubMed: 3352914] [Full Text: https://doi.org/10.1212/wnl.38.4.573]
Pan, T.-C., Zhang, R.-Z., Pericak-Vance, M. A., Tandan, R., Fries, T., Stajich, J. M., Viles, K., Vance, J. M., Chu, M.-L., Speer, M. C. Missense mutation in a von Willebrand factor type A domain of the alpha-3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum. Molec. Genet. 7: 807-812, 1998. [PubMed: 9536084] [Full Text: https://doi.org/10.1093/hmg/7.5.807]
Panades-de Oliveira, L., Rodriguez-Lopez, C., Cantero Montenegro, D., Marcos Toledano, M. D. M., Fernandez-Marmiesse, A., Esteban Perez, J., Hernandez Lain, A., Dominguez-Gonzalez, C. Bethlem myopathy: a series of 16 patients and description of seven new associated mutations. J. Neurol. 266: 934-941, 2019. [PubMed: 30706156] [Full Text: https://doi.org/10.1007/s00415-019-09217-z]
Speer, M. C., Tandan, R., Rao, P. N., Fries, T., Stajich, J. M., Bolhuis, P. A., Jobsis, G. J., Vance, J. M., Viles, K. D., Sheffield, K., James, C., Kahler, S. G., Pettenati, M., Gilbert, J. R., Denton, P. H., Yamaoka, L. H., Pericak-Vance, M. A. Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37. Hum. Molec. Genet. 5: 1043-1046, 1996. [PubMed: 8817344] [Full Text: https://doi.org/10.1093/hmg/5.7.1043]
Speer, M. C., Yamaoka, L. H., Stajich, J., Lewis, K., Pericak-Vance, M. A., Stacy, R., Tandan, R., Fries, T. J. Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A. (Letter) Am. J. Med. Genet. 58: 197-198, 1995. [PubMed: 8533815] [Full Text: https://doi.org/10.1002/ajmg.1320580220]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]
Villar-Quiles, R. N., Donkervoort, S., de Becdelievre, A., Gartioux, C., Jobic, V., Foley, A. R., McCarty, R. M., Hu, Y., Menassa, R., Michel, L., Gousse, G., Lacour, A., and 20 others. Clinical and molecular spectrum associated with COL6A3 c.7447A-G p.(Lys2483Glu) variant: elucidating its role in collagen VI-related myopathies. J. Neuromusc. Dis. 8: 633-645, 2021. [PubMed: 33749658] [Full Text: https://doi.org/10.3233/JND-200577]